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Comment on van der Veer et al, page 1691
Refining prognosis in
BCR-ABL1–positive
ALL
----------------------------------------------------------------------------------------------------Elizabeth A. Raetz1,2 and William L. Carroll3,4
CANCER INSTITUTE; 4NYU LANGONE MEDICAL CENTER
1
HUNTSMAN CANCER INSTITUTE; 2UNIVERSITY OF UTAH; 3NYU
In this issue of Blood, van der Veer et al report the negative prognostic impact
of IKZF1 deletions in children with BCR-ABL1–positive acute lymphoblastic
leukemia (ALL), despite the use of tyrosine kinase inhibitor (TKI) therapy.1
T
reatment of children with BCR-ABL1–
positive ALL has been revolutionized
with the advent of TKI therapy. Historically,
children with BCR-ABL1–positive ALL
were treated with intensive chemotherapy
followed by allogeneic hematopoietic stem
cell transplantation (HSCT), and despite
this, event-free survival rates of ,50%
were observed. With the advent of TKI therapy,
outcomes have improved significantly,2,3
calling for a reassessment of the routine use of
HSCT for BCR-ABL1–positive childhood
ALL. With these emerging data, key questions
remain about how to identify the highest-risk
subsets of children with BCR-ABL1–positive
ALL: how the use of TKI therapy might
modulate this risk and how underlying
pathogenic mechanisms portend a risk for
treatment failure.
Deletions of IKZF1, a gene encoding
the lymphoid transcription factor Ikaros,
which is required for lymphoid
development, are present in .70% of cases
of BCR-ABL1–positive ALL.4 These
alterations have been associated with poor
outcomes both in children with BCRABL1–negative high-risk B-lineage ALL5
and in adults with BCR-ABL1–positive
ALL,6 and this provided rationale for van der
Veer et al to evaluate the prognostic
significance of IKFZ1 deletions in pediatric
patients with BCR-ABL1–positive ALL.1
Importantly, the authors examined 2
sequential cohorts of children, those treated
both before and after the addition of imatinib
to a common chemotherapeutic regimen and
HSCT, to determine how TKI therapy
might affect this risk.
Structure of Ikaros. The N-terminal portion of Ikaros contains a DNA-binding domain with 4 zinc finger motifs. There are
2 zinc finger motifs at the C-terminal end that are essential for the formation of Ikaros homodimers. Ikaros binds directly
to DNA to positively (green) or negatively (red) regulate expression of target genes. Internal deletions in exons 4 to 7 are
common alterations that attenuate the DNA-binding capacity of Ikaros, and these deletions produce a dominantnegative isoform that results in loss of tumor-suppressor function of the WT allele, so that the transcriptional activity is
lost (exons not drawn to actual scale).7
1626
Several key findings emerged from
this study. The authors report that IKZF1
deletions have a negative prognostic impact in
good-risk patients, where risk was defined by
early treatment response, and this cannot be
abrogated fully by the addition of imatinib.
Although better than the 30% overall
4-year disease-free survival (DFS) rate for
historically treated children without a TKI,
the DFS for good-risk patients with IKZF1
deletions was only 55% on the EsPhALL
protocol, which included imatinib. These
findings highlight the need to further
understand underlying pathogenic
mechanisms in BCR-ABL1–positive ALL,
because this subset of patients may benefit
from additional targeted treatment. In
contrast, good-risk, wild-type (WT) IKZF1
patients who received imatinib had outcomes
comparable to those of children with newly
diagnosed ALL without BCR-ABL1 with
DFS rates of ;75%, further supporting the
deferral of HSCT for this group of pediatric
patients.
Interestingly, IKZF1 deletions were not
prognostic in poor-risk patients who received
imatinib. DFS rates of ;50% were observed,
and there were no significant differences in
DFS, overall survival, or relapse incidence
between the WT and IKZF1-deleted poor-risk
subsets. So although outcomes in patients with
poor initial treatment responses did improve
to some degree with TKI therapy, the presence
of an IKZF1 deletion did not alter prognosis
further, which again suggests that other
underlying pathogenic factors are likely to be
present in this group. Alternatively, perhaps
more prolonged imatinib exposure could have
improved outcomes for poor-risk patients.3
Although improvements in refining risk
stratification are certainly warranted, the major
thrust in current research is to define pathways
for targeted therapy. In this regard, the key
question is not whether but how IKZF1
deletions relate to poor outcomes in ALL.
The inferior outcomes suggest that the gene
product or affected pathways play some role in
chemoresistance. The IKZF1 gene encodes for
multiple isoforms, and the full-length product
encodes DNA-binding zinc finger domains,
a dimerization domain, and an activation
domain (see figure).7 Ikaros proteins function
to positively and negatively alter the
transcription of downstream pathways in
concert with activator or repressor complexes.
IKZF1 deletions fall into 3 major categories:
BLOOD, 13 MARCH 2014 x VOLUME 123, NUMBER 11
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those that disrupt the protein coding exons
completely (null mutations) on one allele,
intragenic deletions that impact exons 4 to 7
that result in dominant-negative isoforms,
and biallelic deletions that result in a null
phenotype. Single base mutations also occur,
many of which would be predicted to impair
function.5
Although the contribution of each allele
might vary, the functional impact of such
alterations on the Ikaros pathway might be
predicted to be (from most to less severe)
biallelic/null, dominant negative, and
haploinsufficient. In this scenario, the null
and dominant-negative isoforms might be
predicted to be associated with a worse
prognosis, yet paradoxically, it was only
haploinsufficient cases that conferred an adverse
prognosis in the study by van der Veer et al. The
authors speculate that this might be due to cases
with large deletions, including monosomy 7,
where the disruption of other pathways might
contribute to the poor prognosis.
These intriguing observations need to be
validated, because no such distinctions have
been seen in previous studies6 and monosomy 7
deletions make up a minority of the IKZF1
disruptions. However, there is some evidence
that the poorer prognosis of IKZF1 deletions
might be related to the company it keeps. A
recent report by this same group showed that
additional copy-number alterations may confer
a worse prognosis compared with cases with
IKZF1 deletion alone.8 Finally, a very
provocative report by Uckun et al found
no evidence of diminished Ikaros protein
expression or function in high-risk ALL,
including BCR-ABL1–positive ALL.9 These
authors suggest that the poor outcomes
associated with IKFZ1 deletions in ALL
could be a reflection of underlying genomic
instability in aggressive leukemic clones rather
than lost or diminished IKFZ1 function per se.
In summary, van der Veer et al have
demonstrated that IKFZ1 deletions define
a subset of BCR-ABL1–positive pediatric
patients with unfavorable outcomes, despite
treatment with contemporary TKI-based
therapy, providing information that could
potentially be used to alter treatment in
the future. Their study also highlights the
heterogeneity of this disease as well as the
complexity of studies of IKFZ1 as a prognostic
marker, because deletions have not been
uniformly associated with poor outcomes in all
subsets of patients.8,10 Questions still remain
of whether outcome differences are directly
related to loss of IKFZ1 gene function vs
a reflection of other underlying pathogenic
mechanisms. This study also provides further
evidence for the good outcomes that can be
achieved among favorable subsets of
BCR-ABL1–positive patients with TKI therapy,
supporting deferral of HSCT for this group.
Conflict-of-interest disclosure: The authors declare
no competing financial interests. n
REFERENCES
1. van der Veer A, Zaliova M, Mottadelli F, et al. IKZF1
status as a prognostic feature in BCR-ABL1-positive
childhood ALL. Blood. 2014;123(11):1691-1698.
2. Biondi A, Schrappe M, De Lorenzo P, et al.
Imatinib after induction for treatment of children and
adolescents with Philadelphia-chromosome-positive acute
lymphoblastic leukaemia (EsPhALL): a randomised, openlabel, intergroup study. Lancet Oncol. 2012;13(9):936-945.
3. Schultz KR, Bowman WP, Aledo A, et al. Improved
early event-free survival with imatinib in Philadelphia
chromosome-positive acute lymphoblastic leukemia:
a children’s oncology group study. J Clin Oncol. 2009;
27(31):5175-5181.
4. Iacobucci I, Storlazzi CT, Cilloni D, et al.
Identification and molecular characterization of recurrent
genomic deletions on 7p12 in the IKZF1 gene in a large
cohort of BCR-ABL1-positive acute lymphoblastic
leukemia patients: on behalf of Gruppo Italiano Malattie
Ematologiche dell’Adulto Acute Leukemia Working Party
(GIMEMA AL WP). Blood. 2009;114(10):2159-2167.
5. Mullighan CG, Su X, Zhang J, et al; Children’s
Oncology Group. Deletion of IKZF1 and prognosis in
acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):
470-480.
6. Martinelli G, Iacobucci I, Storlazzi CT, et al.
IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute
lymphoblastic leukemia are associated with short diseasefree survival and high rate of cumulative incidence of
relapse: a GIMEMA AL WP report. J Clin Oncol. 2009;
27(31):5202-5207.
7. Li Z, Perez-Casellas LA, Savic A, Song C, Dovat S.
Ikaros isoforms: the saga continues. World J Biol Chem.
2011;2(6):140-145.
8. Palmi C, Valsecchi MG, Longinotti G, et al. What
is the relevance of Ikaros gene deletions as a prognostic
marker in pediatric Philadelphia-negative B-cell precursor
acute lymphoblastic leukemia? Haematologica. 2013;98(8):
1226-1231.
9. Uckun FM, Ma H, Ishkhanian R, et al. Constitutive
function of the Ikaros transcription factor in primary
leukemia cells from pediatric newly diagnosed high-risk
and relapsed B-precursor ALL patients. PLoS ONE. 2013;
8(11):e80732.
10. van der Veer A, Waanders E, Pieters R, et al.
Independent prognostic value of BCR-ABL1-like signature
and IKZF1 deletion, but not high CRLF2 expression, in
children with B-cell precursor ALL. Blood. 2013;122(15):
2622-2629.
© 2014 by The American Society of Hematology
l l l LYMPHOID NEOPLASIA
Comment on Chambwe et al, page 1699
The
DNA methylome: a novel biomarker
----------------------------------------------------------------------------------------------------Izidore S. Lossos1
1
UNIVERSITY OF MIAMI
In this issue of Blood, Chambwe and colleagues demonstrate the presence of
promoter methylation variability in diffuse large B-cell lymphomas (DLBCLs).1
This methylation variability correlates with the expression of specific genes and is
associated with distinct survival following standard therapy—a finding that has
numerous implications for our understanding of the pathogenesis of these tumors.
D
LBCL, the most common subtype of
non-Hodgkin lymphoma, is highly
diverse from both biological and clinical
standpoints. DLBCL pathogenesis is
a complex multistep process that involves
collaboration between the biological programs
of normal B cells and acquired somatic
tumor–associated genetic aberrations,
including chromosomal translocations, gene
amplifications, insertions/deletions and
mutations, and posttranscriptional regulation
by aberrantly expressed microRNAs.2-4 Some
of these genetic aberrations, as well as the
expression of individual genes or gene
BLOOD, 13 MARCH 2014 x VOLUME 123, NUMBER 11
signatures, may also modulate tumor
aggressiveness and response to therapy, thus
serving as biomarkers that predict or correlate
with patients’ survival.5
Epigenetic changes, including epigenetic
modifications of chromatin as well as aberrant
hypermethylation or hypomethylation of
promoters, may also contribute to lymphoma
pathogenesis. Indeed, global DNA
hypomethylation or focal changes in the
methylation of promoters are observed in
cancer. Previous methylome studies in
DLBCL identified specific patterns of
abnormal methylation, varying depending
1627
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2014 123: 1626-1627
doi:10.1182/blood-2014-01-547570
Refining prognosis in BCR-ABL1−positive ALL
Elizabeth A. Raetz and William L. Carroll
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